Therapeutic strategies aimed at long-term suppression of viral replication through a combination of highly active antiretroviral therapy (HAART) and immune modulation, offer the best hope for HIV-1 infected patients worldwide. Clinical experience suggests that life-long HAART is generally not feasible but that a subset of patients may benefit from a limited period of HAART followed by strategic treatment interruption (STI). Clinical trials, some in early infection, are already ongoing to test this hypothesis. What is lacking from these trials -and what the UAB AIEDRP proposes to undertake -is a comprehensive, dynamic assessment of the molecular virologic and immunologic responses to HAART + STI (+/- vaccine) regimens as a means to rationally interpret and design long-term therapeutic strategies. The UAB AIEDRP proposes, for the first time, a coordinated, full viral genome-length assessment of CTL and neutralizing antibody control and escape in acute HIV-1 infection, including a systematic evaluation of the impact of therapy. We propose also to evaluate the initial innate immune responses and their impact upon subsequent HIV -specific immune responses. Underpinning these aims will be an emphasis on immunogenetic correlates of host immune control. These studies will be conducted in treatment-naive patients and in the context of two new clinical trial strategies: The first protocols (UAB201-3) are designed for patients from developed countries and aim to maximize the virus containment period while minimizing HAART exposure. The second strategy (UAB301) is designed for patients from developing countries where complicated and prolonged treatment is impractical but where there is an urgent need to alter viral load and clinical outcome by brief periods of therapy. UAB201-3, conducted at U.S. sites, will evaluate combinations of HAART, STI, therapeutic vaccination, and selective T-lymphocyte suppression, to test the hypothesis that immune-based therapies will result in sustained HIV -1 containment off therapy that can be correlated with specific measures of anti-HIV immunity. UAB301, conducted in Zambia, will be comprised of brief (3-month) HAART and will test the hypothesis that therapy initiated early after viral infection will reduce viral load setpoint. We will anchor and interpret our clinical observations with a detailed molecular assessment of viral dynamics, viral genetics, immunogenetics, and host immune responses. These studies will provide new insights into HIV-1 pathogenesis and early immune control and a comprehensive set of virologic and immunologic data important to the rational design of HAARTISTI/immunomodulation trials in both developed and developing countries. Finally, our proposal involves collaborations with other AIEDRP units where an important exchange of patient specimens, scientific expertise, technology, and data will continue.